Modern imaging techniques are rapidly improving the diagnostic accuracy and clinical management of pathological disorders. Among the more prevalent imaging technologies currently available are ultrasound, magnetic resonance imaging (MRI), computerized tomography (CT), and positron emission tomography (PET). Radiographic procedures, such as computed tomography and positron emission tomography, operate by detecting and mapping differences in the composition of a target object. Unfortunately CT and PET utilize ionizing radiation and require relatively expensive equipment. Conversely, MRI and ultrasound do not require ionizing radiation and, at least in the case of ultrasound imaging, utilize relatively inexpensive equipment.
In magnetic resonance visualization, advantage is taken of the fact that some atomic nuclei, such as, for example, hydrogen nuclei or fluorine nuclei have both nuclear spin and nuclear magnetic moment, and therefore can be manipulated by applied magnetic fields. Traditional MRI comprises the use of a magnetic field that is established across a body to align the spin axes of the nuclei of a particular chemical element in the direction of the magnetic field. The aligned, spinning nuclei execute precessional motions around the aligning direction of the magnetic field. For the aligned, spinning nuclei the frequency at which they precess around the direction of the magnetic field is a function of the particular nucleus which is involved and the magnetic field strength. The selectivity of this precessional frequency with respect to the strength of the applied magnetic field is very sharp and this precessional frequency is considered a resonant frequency.
After alignment or polarization of the selected nuclei, a burst of radio frequency energy at the resonant frequency is radiated at the target body to produce a coherent deflection of the nuclei spin alignment. When the deflecting radio energy is terminated, the deflected or disturbed spin axes are reoriented or realigned, and in this process radiate a characteristic radio frequency signal which can be detected by an external coil and then resolved by the MRI system to establish image contrast between different types of tissue in the body.
Contrast agents for MRI must possess a substantially different concentration of the nuclei used as a basis for scanning. For example, in a hydrogen scanning system, an agent substantially lacking hydrogen can be used. Conversely, in a magnetic visualization system that scans for a physiologically minor nucleus such as the fluorine nuclei, a substance with a high concentration of that nucleus would provide the appropriate contrast.
Imaging or contrast agents may be introduced into the body space in various ways depending on the imaging requirement. In the form of liquid suspensions or emulsions they may be placed into the area of interest by oral ingestion or injection into the bodily space (either directly or by channeling through selected vessels). Typically, the contrast agents are transported by the blood or other fluids to the regions of interest. A suitable contrast agent must be biocompatible, that is non-toxic and chemically stable, not absorbed by the body or reactive with the tissue, and eliminated from the body within a short time.
In ultrasound imaging, ultrasonic waves are transmitted into an object or patient via a transducer. As the sound waves propagate through the object or body, they are either reflected or absorbed by tissues and fluids. Reflected ultrasonic waves are then received by the transducer and converted into electrical signals from which an image is generated. The acoustic properties of the tissues and fluids determine the contrast which appears in the resulting image.
Ultrasound imaging, therefore, makes use of differences in tissue density and composition that affect the reflection of sound waves by those tissues. Images are especially sharp where there are distinct variations in tissue density or compressibility, such as at tissue interfaces. Interfaces between solid tissues, the skeletal system, and various organs and/or tumors are readily imaged with ultrasound.
Accordingly, in many imaging applications ultrasound performs suitably without use of contrast enhancement agents; however, for other applications, such as visualization of flowing blood in tissues, there have been ongoing efforts to develop agents to provide contrast enhancement. One particularly significant application for these contrast agents is in the area of vascular imaging. Such ultrasound contrast agents can improve imaging of flowing blood in the brain, heart, kidneys, lungs, and other tissues. This, in turn, facilitates research, diagnosis, surgery, and therapy related to the imaged tissues. A blood pool contrast agent also allows imaging on the basis of blood content (e.g., tumors and inflamed tissues) and can aid in the visualization of the placenta and fetus by enhancing only the maternal circulation.
In this regard, a variety of ultrasound contrast enhancement agents have been proposed. The most successful agents generally consist of microbubbles that can be injected intravenously. In their simplest embodiment, microbubbles are miniature bubbles containing a gas, such as air, and are formed through the use of foaming agents, surfactants or other film forming agents, or encapsulating agents. More advanced formulations of microbubbles, such as those described in U.S. Pat. No. 5,605,673, comprise fluorochemical gases or vapors. In any event, the microbubbles provide a physical object in the flowing blood that is of a different density and possesses a much higher compressibility than the surrounding fluid tissue and blood. As a result, these microbubbles act as good reflectors of ultrasound energy and can easily be imaged.
While contrast agents for both ultrasound and magnetic visualization can substantially enhance the resolution of physiological structures and highlight deficiencies in blood flow through tissue, their use has not, at least prior to the instant application, allowed for the reliable quantitative assessment of blood flow. For example, prior to the instant invention, common ways of determining the rate of blood flow included Doppler ultrasound or by introduction of a bolus of an imagable contrast agent into a coronary artery through a catheter and measurement of the transit time of the bolus through the heart. Unfortunately, Doppler measurements of vascular flow have not proven efficient enough to provide the necessary accuracy in clinical situations. Conversely, although more accurate, the introduction of a bolus of contrast agent into a coronary artery may lead to complications. Moreover, as the technique requires placement of a catheter directly into the coronary artery, it is extremely invasive. This substantially increases patient discomfort, burden on hospital resources and precludes the use of the procedure on all but the most serious cases. Perhaps most importantly, while the aforementioned techniques may be used to give a rough estimate of blood flow through the heart or in a major artery, current procedures are unable to accurately quantitate the rate of blood flow or perfusion within a particular tissue; i.e. within the liver, kidney or heart.
Accordingly, it is an object of the present invention to provide methods for the accurate determination for the rate or amount of blood flow through a particular target region as a factor of time.
It is another object of the present invention to provide for the accurate measurement of the perfusion rate of a selected target tissue.
It is still another object of the present invention to accurately provide for the noninvasive determination of blood flow through the heart.
It is yet another object of the present invention to provide for the accurate measurement of rate of fluid flow using ultrasound imaging or magnetic visualization techniques.